Cardiovascular diseases mainly include heart paralysis, angina pectoris (myocardial infarction), arrhythmia, hemorrhagic heart failure, hypertension, stroke, congenital cardiac defect, rheumatic heart disease, and the like. Among those diseases, heart paralysis, stroke and hypertension are three most common diseases. Usually, possible factors causing risks of cardiovascular diseases are not present independently, but co-existent.
Isosorbide dinitrate, which is also known as Xiaoxintong, is mainly used for preventing and treating angina pectoris. In recent years, however, it also became a primary drug for treating heart failure. It acts on the specific receptor in the vascular smooth muscles and releases inorganic nitrate to relax the smooth muscles. A small dose of isosorbide dinitrate can expand the veins, and a large dose of isosorbide dinitrate can expand both the arteries and the veins. The expansion of the vein system can lower the preload and reduce the volume of the left ventricle so as to enhance the contractility of the cardiac muscles. Meanwhile, the reduction of the diastolic pressure in the heart chambers also lowers the resistance of the subendocardial coronary arteries, so that the blood-supply ability of the cardiac muscles is improved, the contractility of the cardiac muscles is enhanced, and the heart failure is alleviated. It can act instantly and has a reliable therapeutic effect, and is more convenient than other vasodilator drugs that need to be injected, such as phentolamine, nitroprusside sodium and the like. Therefore isosorbide dinitrate is a primary drug for treating heart failure.
However, a tolerance to isosorbide dinitrate may be caused if this drug is administered continuously. Consequently, the therapeutic effect may be diminished or disappear. It is mentioned in Drugs for Heart primarily translated by Gao Wei et al. (4th edition, Liaoning Education Press, September of 1999, page 48) that if long acting nitric acid ester drugs are regularly administered for a long period of time without intermission or dosing peak period, it is very easy for this kind of drugs to cause tolerance, and the effect of said drugs cannot be persistent. If isosorbide dinitrate is administered four times a day in a dosage of 30 mg each time for a long period of time, the effect thereof on treating angina pectoris will be quickly weakened because of the tolerance. This literature and all publications or literatures as mentioned below are incorporated into the specification by reference.
Bisoprolol is a β1 receptor blocking agent having high affinity and selectivity to receptor of heart. Compared with β receptor blocking agents that do not have selectivity, Bisoprolol can prevent adverse effects on pulmonary functions, blood lipid and peripheral circulation caused by β2 receptor blocking.
However, the oral administration of Bisoprolol will cause some adverse effects. Liu Guoshu et al. (Clinical Observations of 228 Patients with Primary Hypertension Treated with Bisoprolol, Journal of Cardiopulmonary Vascular Diseases, 3rd issue, vol. 18, 1999, pages 179 to 182) reported that the oral administration of Bisoprolol had good pressure-reducing effects but would greatly affect the heart rate. The average reduction of the heart rate after the treatment was 15.1%. Moreover, the higher the dosage was, the lower the heart rate would be. Common adverse effects, such as sinoatrial bradycardia, complete right bundle branch block, atrial premature, nausea and acratia, and short P-R interval syndrome, were exhibited in some patients. It shows that Bisoprolol should be administrated orally with discretion to the patients with a slow heart rate.
People also tried to treat angina pectoris by the combination of Bisoprolol with long acting nitric acid ester drugs.
Mireille C. M. Portegies et al. (Mireille C. M. Portegies, Jan Brouwer, Louis L. M. V. D. Ven, Jan W. Viersma, and Kong I. Lie, “Effect of Bisoprolol and Isosorbide Dinitrate on the Circadian Distribution of Myocardial Ischemia”, Current Therapeutic Research, 1995, (56), 1225-1236) compared the results of treating athletic type angina pectoris and myocardial ischemia with isosorbide dinitrate and Bisoprolol independently and the combination thereof. Bisoprolol was administered orally once a day in a dosage of 10 mg, and isosorbide dinitrate was administered orally thrice a day in a dosage of 20 mg. The drugs were administered continuously for 4 weeks. Results showed that the effect of the combination of the drugs was just the addition of the effects of said two independent drugs and did not exhibit a significant synergistic effect on the symptoms studied.
O. DE Divitiis et al. (O. DE Divitiis, V. Liguori, S. Di Somma, et al., “Bisoprolol in the Treatment of Angina Pectoris: a Double Blind Comparison with Verapamil”, European Heart Journal, 1987, 8 (Suppl. M), 43-54)) compared the pharmaceutical effect of the combination of Bisoprolol and isosorbide dinitrate (1:4 to 1:2) on the treatment of angina pectoris with that of the combination of Isoptin and isosorbide dinitrate (6:1 to 9:1) and discovered that like Isoptin, Bisoprolol was also effective on treating myocardial ischemia and the patients had a good tolerance to it.
A transdermal patch is a pharmaceutical formulation that can be percutaneously applied. Liang Bingwen indicates in Transdermal Drug Delivery Formulation (China Medical-Pharmaceutical Science & Technology Publishing House, published in September 1992, pages 13-14) that compared with conventional administering methods, the transdermal drug delivery system has the following characteristics. (1) The drug can enter the body at a constant rate during a long period of time, which is similar to a long term intravenous drip. (2) The first pass effect of the liver and the interference and degradation effects of the gastrointestinal tract factors can be avoided. These factors are also main reasons for individual effective differences caused by the oral administration of drugs. The transdermal drug delivery system can reduce individual differences (3) The permeating rate of drugs is the same as the rate of elimination in vivo. A constant and effective plasma drug concentration can be maintained. Consequently, the fluctuation of plasma drug concentration caused by other administering methods can be avoided, and adverse effects of the drugs can be decreased. (4) It's very convenient for patients to use the transdermal drug delivery system. It is more suitable for patients to whom the oral administration is not appropriate and patients who need to administer a drug for a long period of time.
There are literatures reporting transdermal patches containing either isosorbide dinitrate or Bisoprolol alone (Hidaka Osafumi, Isosorbide Dinitrate-Containing Patch, Chinese Patent No.: ZL98800181.0, Tateishi Tetsuro, et al., Adhesive Patch, WO2005011662; SAEKI YUJI, et al., Bisoprolol-Containing Plaster, JP2003313122).
However, the prior arts have not disclosed any transdermal pharmaceutical formulations containing both isosorbide dinitrate and Bisoprolol by far.
The inventors of this invention have discovered that in transdermal patches containing isosorbide dinitrate and Bisoprolol at special ratios, said drugs exhibit an unexpected synergistic effect. Compared with transdermal patches containing either isosorbide dinitrate or Bisoprolol alone, the combination of isosorbide dinitrate and Bisoprolol at said special ratios exhibits excellent effects on preventing and treating a variety of heart diseases and a better pressure-reducing effect and improves the arrhythmia caused by transdermal patches containing either isosorbide dinitrate or Bisoprolol. Therefore the inventive patches show advantages in the treatment of cardiovascular diseases.
Contents of the Invention
The object of this invention is to provide a transdermal patch comprising isosorbide dinitrate and Bisoprolol at a special ratio for treating cardiovascular diseases. Isosorbide dinitrate and Bisoprolol at said ratio exhibit a synergistic effect.
Consequently, this invention relates to a transdermal patch in the form of a complex layer comprising a backing layer, a drug-reservoir layer comprising pharmacologically active ingredients and pharmaceutically acceptable adjuvants, and a release liner covering the drug-reservoir layer, characterized in that the drug-reservoir layer comprises isosorbide dinitrate and Bisoprolol at a ratio of 1:3 to 3:1 by weight, preferably 1.2 to 1.8:1, most preferably 1.4 to 1.6:1 by weight.
In the transdermal patch according to this invention, the backing layer consists of back supporting materials well known to a person skilled in the art, such as an aluminum foil, polyethylene terephthalate, polyethylene or non-woven fabrics.
In the transdermal patch according to this invention, the pharmaceutically acceptable adjuvants include a permeation enhancer and a polymeric matrix, wherein the polymeric matrix is, for example, selected from the group consisting of an acrylic pressure-sensitive adhesive and a combination of an acrylic pressure-sensitive adhesive with an Eudragit-type acrylic resin.
In this application, the term “an acrylic pressure-sensitive adhesive” refers to a polymer well known in the art formed by copolymerizing acrylic acid and derivatives thereof. Said polymer has a saturated carbon-hydrogen primary chain and an ester side chain. A sticky acrylic pressure-sensitive adhesive can be produced by modifying comonomers and side chain groups. Common monomers include acrylic acid, butyl acrylate, 2-ethylhexyl acrylate, vinyl acetate, 2-hydroxyethyl acrylic acid and the like. The polymerization reaction can be performed in a solution (Liang Bingwen, Transdermal Drug Delivery Formulation, China Medical-Pharmaceutical Science & Technology Publishing House, published in September 1992, pages 230-232; Yang Yukung, Pressure-Sensitive Adhesives, Chapter 5, An Acrylic Ester Pressure-Sensitive Adhesive, Science Press, published in May of 1991, pages 148-210; and Wang Shuming, CN1640500A).
With regard to said “Eudragit-type acrylic resin”, non-limiting examples include Eudragit® L100, Eudragit® 5100, Eudragit® RL100, Eudragit® RS100, Eudragit® E100, Eudragit® L100-55, Eudragit® E PO, Eudragit® RL PO, Eudragit® RS PO and the like manufactured by Röhm Co. Ltd. (Germany).
In the preferred embodiments of the transdermal patch according to this invention, the polymeric matrix is a mixture of an acrylic pressure-sensitive adhesive with an Eudragit-type acrylic resin.
In this application, the term “permeation enhancer” is a substance well known in the art that can overcome the barrier effect of the skin and increase the transdermal flux of a drug or the transdermal amount of a drug, including surfactants, organic solvents, such as alcohols, e.g. propylene glycol (PG), esters, dimethyl sulfoxide and analogs thereof, azone compounds, organic acids and esters or amides thereof, etc. (Liang Bingwen, Transdermal Drug Delivery Formulation, Chapter 5, Transdermal Permeation Enhancers and its application thereof, China Medical-Pharmaceutical Science & Technology Publishing House, published in September 1992, pages 116-164). Non-limiting examples of said permeation enhancers include isopropyl myristate, Azone, propylene glycol and the like and a mixture thereof.
In one embodiment of the transdermal patch according to this invention, the drug-reservoir layer consists of, based on the total weight of the drug-reservoir layer, the following substances:
isosorbide dinitrate1-17%Bisoprolol1-17%Eudragit RS1000.1-30%acrylic resin pressure-sensitive adhesive (in dry basis)30-80%propylene glycol0-25%isopropyl myristate4.5-22%Azone1.5-7%and the sum thereof is 100%.
In one preferred embodiment of the transdermal patch according to this invention, the drug-reservoir layer consists of, based on the total weight of the drug-reservoir layer, the following substances:
isosorbide dinitrate2.5-15%Bisoprolol2-8%Eudragit RS1000.5-25%acrylic resin pressure-sensitive adhesive (in dry basis)45-65%isopropyl myristate6-10%Azone4-6%and the sum thereof is 100%.
In one particularly preferred embodiment of the transdermal patch according to this invention, the drug-reservoir layer consists of, based on the total weight of the drug-reservoir layer, the following substances:
isosorbide dinitrate3.6-10%Bisoprolol2.6-6%Eudragit RS1003-25%acrylic resin pressure-sensitive adhesive (in dry basis)45-65%isopropyl myristate6-10%Azone4-6%and the sum thereof is 100%.
In another embodiment of the transdermal patch according to this invention, the drug-reservoir layer consists of the following substances by weight.
isosorbide dinitrate0.5-2parts by weightBisoprolol0.4-1.1parts by weightEudragit RS1000.1-3.5parts by weightacrylic resin pressure-sensitive adhesive5-10parts by weight(in dry basis)isopropyl myristate0.5-2parts by weightAzone0.2-0.6part by weight.
In another embodiment of the transdermal patch according to this invention, the drug-reservoir layer consists of the following substances:
isosorbide dinitrate0.5-1.3parts by weightBisoprolol0.35-0.8part by weightEudragit RS1000.5-3.5parts by weightacrylic resin pressure-sensitive adhesive6-8parts by weight(in dry basis)isopropyl myristate1-1.5parts by weightAzone0.2-0.6part by weight.
In another embodiment of the transdermal patch according to this invention, the drug-reservoir layer consists of the following substances:
isosorbide dinitrate0.5-0.7part by weightBisoprolol0.4part by weightEudragit RS1000.25-3.5parts by weightacrylic resin pressure-sensitive adhesive6-8parts by weight(in dry basis)isopropyl myristate1-1.5parts by weightAzone0.2-0.6part by weight.
In another embodiment of the transdermal patch according to this invention, the drug-reservoir layer consists of the following substances:
isosorbide dinitrate0.6part by weightBisoprolol0.4part by weightEudragit RS1003parts by weightacrylic resin pressure-sensitive adhesive6-8parts by weight(in dry basis)isopropyl myristate1-1.5parts by weightAzone0.4part by weight.
In another preferred embodiment of the transdermal patch according to this invention, the drug-reservoir layer consists of the following substances:
isosorbide dinitrate1.0-1.5parts by weightBisoprolol0.8part by weightEudragit RS1000.25-3.5parts by weightacrylic resin pressure-sensitive adhesive6-8parts by weight(in dry basis)isopropyl myristate1-1.5parts by weightAzone0.2-0.6part by weight.
In another embodiment of the transdermal patch according to this invention, the drug-reservoir layer consists of the following substances:
isosorbide dinitrate1.2parts by weightBisoprolol0.8part by weightEudragit RS1003parts by weightacrylic resin pressure-sensitive adhesive6-8parts by weight(in dry basis)isopropyl myristate1-1.5parts by weightAzone0.4part by weight.
The transdermal patch according to this invention can be produced by any techniques known in the art, such as manufacture processes indicated by Liang Bingwen in Transdermal Drug Delivery Formulations (China Medical-Pharmaceutical Science & Technology Publishing House, published in September 1992, pages 328-337), such as, dissolving isosorbide dinitrate and Bisoprolol in an organic solvent, mixing the solution obtained with a solution comprising an permeation enhancer, mixing the obtained mixture with a solution comprising a polymeric matrix, coating the resultant to a back supporting material by a coating equipment comprising a roller coating type, a doctor knife coating type or by hand-coating, and then drying it. After that, the various layers of the product are laminated, died cut and packed.
The structure of the transdermal patch according to this invention can be a membrane-reservoir type, skeleton-controlled release type, and adhesive-controlled release type, wherein the drug-reservoir layer can be in the form of a mono-layer or multi-layered complex. Specific structures comprise, for example, a backing layer, a drug-reservoir layer, a drug release rate-controlling membrane layer, a pressure-sensitive adhesive layer (comprising a minor amount of the drugs or free of a drug), and a covering layer (FIG. 1); a backing layer, a drug-reservoir layer and a covering layer (FIG. 2); and a backing layer, a drug-reservoir layer, a drug release rate-controlling pressure-sensitive adhesive layer (comprising a minor amount of the drugs or free of a drug), and a covering layer (FIG. 3).
Tests of the transdermal patch according to this invention on animals show that the transdermal patch according to this invention can reduce the elevation of T wave of cardiogram, the increase of the level of myocardial enzyme in blood serum, the extension of the range of myocardiac infarction caused by ligating the coronary artery in animals. The results show that the transdermal patch according to this invention exhibits good therapeutic and preventive effects on several heart-diseases. In addition, animal tests also show that it not only has a better effect on reducing the blood pressure than the application of the patch containing either isosorbide dinitrate or Bisoprolol, but also improves or does not worsen the arrhythmia caused by the application of the patch containing only one of isosorbide dinitrate and Bisoprolol. Thus, it is shown that the combination of isosorbide dinitrate and Bisoprolol in the transdermal patch according to this invention, exhibits a considerable synergistic effect in the treatment of cardiovascular diseases. The combination of isosorbide dinitrate and Bisoprolol at said ratios has certain advantages in treating cardiovascular diseases.
The transdermal patch according to this invention is suitable for local application in the treatment or prevention of hypertension, coronary heart disease, atherosclerosis, myocardial ischemia or angina pectoris etc. in mammals. Generally, the dosage per day is based on the total weight of isosorbide dinitrate and Bisoprolol, 0.05-20 mg/kg body weight, preferably 0.5-10 mg/kg body weight, and particularly preferred 1-5 mg/kg body weight.